PROJECT ABSTRACT Among the most intractable pregnancy pathologies are preeclampsia, intrauterine growth restriction (IUGR) and gestational diabetes (GDM), all of which are associated with placental dysfunction. The onset of these disorders occurs likely in late 1st and early 2nd trimester before the onset of the clinical manifestations. Currently no tools to assess placental health/function in these crucial trimester periods have been developed that could be utilized for routine clinical diagnosis. We will take advantage of the continuous release of placental debris (including exosomes) into the maternal circulation. We will apply cutting-edge high throughput lipidomic technologies that provide measurements of the lipidome in exosomes of placental origin in the circulation of pregnant mothers. We propose two Aims intended to move the field towards assessment of placental health/ function throughout pregnancy and to generate clinically useful tests for identifying and monitoring significant placental pathologies. In Aim 1, we will undertake a large scale longitudinal study to assess lipid profiles in circulating placental exosomes isolated from uncomplicated pregnancies. This will yield baseline gestational time course profiles for multiple lipid species, sufficient for comparison with data from pathological pregnancies. Aim 2 will entirely focus on the lipidome of circulating placental exosomes derived from pregnancies complicated by preeclampsia, IUGR and GDM. This aim will develop a new generation of lipid biomarkers that can be integrated with maternal demographic and environmental factors already known to associate with increased risk. This innovation will be achieved as a result of the interpretation of lipid biomarkers in the context of the mother and fetal ?environment?. Our approach will integrate our discovered lipid biomarkers that hold promise as being predictive of pregnancy outcomes with the ?environmental and maternal? datasets using new iterative statistical modeling to identify pregnancy that are at risk of adverse outcomes. The strong investigative team, composed of lipid biochemists, a biostatistician, maternal-fetal medicine specialists and placental biologists, is delivering these new tools in the research setting and is poised to generate new lipid biomarkers for clinical measurement of placental health and function.